Switchable synthesis of natural-product-like lawsones and indenopyrazoles through regioselective ring-expansion of indantrione

Lawsones and indenopyrazoles are the prevalent structural motifs and building blocks in pharmaceuticals and bioactive molecules, but their synthesis has always remained challenging as no comprehensive protocol has been outlined to date. Herein, a metal-free, ring-expansion reaction of indantrione with diazomethanes, generated in situ from the N-tosylhydrazones, has been developed for the synthesis of lawsone and indenopyrazole derivatives in acetonitrile and alcohol solvents, respectively. It provides these valuable lawsone and pyrazole skeletons in good yields and high levels of diastereoselectivity from simple and readily available starting materials. DFT calculations were used to explore the mechanism in different solutions. The synthetic application example also showed the prospects of this method for the preparation of valuable compounds.

1) "Since scaffold generation is pivotal during the early stage of drug discovery, issues like chemical efficiency, and easy diversification are crucial in process development" Process development is ambiguous in this context -is it meant as large-scale drug manufacturing, or as reaction development?
2) "classical homology method" --> "classical homologation method" 3) "for generate structurally" --> "for generation of structurally" 4) Please expand Scheme 1 to include specific illustrations of previous approaches (e.g. from refs 4, 5, 6, 7). This will allow readers to better gauge the novelty of the current work. 5) " imbedded" --> "embedded" 6) "that aren't readily available" --> "that are not readily available" 7) "A small amount of selective by-product 4a was generated in 15% yield. " This is confusing -how can a by-product be selective? 8) "two different chemoselective products" -I suggest leaving out 'chemoselective'. 9) " Table 1 Optimized reaction conditions." -I do not think that this caption is appropriate, perhaps 'reaction optimization'? 10) "To verity the relative configurations" --> "To verify the relative configurations" 11) "facilely" -spelling 12) " labeling" -spelling 13) Page 8, line 120: " using lawsone product 4a as the starting material, the reaction proceeded under the 121 standard conditions in an alcohol solution." The phrasing here suggests that the reaction worked, but the scheme clearly shows that this reaction did not produce 5a. Please consider rephrasing. 14) Page 9, line 125: "the yield of the indenopyrazolone product increased gradually upon increasing the proportion of acetonitrile. " Scheme 4 shows the complete opposite -that the yield of the indenopyrazolone increased with the proportion of ethanol. 15) Page 9, line 127: "On the contrary, the yield of lawsones increased upon 127 increasing the methanol proportion" Again, the complete opposite is shown in Scheme 4, eq 4. Also, the scheme shows ethanol was used, but the text mentions methanol -which was actually used? 16) Energies are quoted in text and schemes to 2 d.p. precision -this implies much higher accuracy than DFT can deliver. I believe the energies should be quoted to 1 d.p. precision. 17) Scheme 5 -the highest barrier in DFT calculated pathway is 22.1 kcal/mol, which suggests the reaction can proceed at room temperature or maybe slightly above, but the reaction is run at 80C. Please speculate on the reasons behind this discrepancy. 24) "Scheme 7 Proposed machenism." --> spelling Supporting Information: 25) Integration in all of the 1H NMR copies should be adjusted. The integration curves must have flat ends, indicating that the integration bounds have been set properly -this is not the case in most copies provided by the authors. Also, it makes no mathematical sense integrating parts of an overlapping multiplet -overlapping peaks should be integrated as one large multiplet. 26) Main text needs a comment on the purity of the p-NO2 compound in SI page 74. This sample should be repurified, an updated NMR collected and updated yield after repurification reported in text. Also, NMR copy should show all of the NMR range, including the 0 -2ppm range, just like most other NMR copies in this manuscript. 27) Page 80 of the SI -the integration of the methyl peak in the 1H NMR is particularly bad. It is obvious only a tiny sliver of the actual peak has been integrated. Please reprocess the NMR.
28) Page 84 -CN-compound needs repurification and yield adjustment, NMR clearly shows impure sample. 29) Page 104 -compound needs repurification and yield adjustment, NMR clearly shows impure sample. 30) Gaussian reference is incomplete -their website provides the preferred format for referencing the software. 31) I strongly encourage the authors to upload their computational output files as a dataset to a site like https://zenodo.org/ , or a similar open data repository and include the DOI link the dataset in the revised manuscript. Alternatively, the output files could be included as a data archive and attached as part of the SI. Sharing the output files makes the work more accessible and easier to reproducible and build upon, thus increasing its impact. The Cartesian coordinates are difficult to use, contains much more limited data, and presents an unnecessary barrier to reproduction of the results.
The paper by Hu et al. provides an interesting synthetic and mechanistic study of lawsone and indenopyrazole derivatives via ring-expansion reactions. The paper has some issues with spelling, data interpretation and reporting and analytical data. However, after these issues are addressed, I believe the paper would be suitable for publication in Nature Communications Chemistry.
Reviewer #2 (Remarks to the Author): The authors describe herein the switchable synthesis of lawsones and indenopyrazoles via regioselective ring-expansion of indantrione with aldehydes using an umpolung strategy. The chemistry developed in this manuscript is intriguing and features profound utility potential for assembling such skeletons, which should of interest to the readers of Communications Chemistry. However, the computational mechanistic studies for compound 5a seem to be unreasonable as the highest energy barrier is up to 57.49 kcal/mol (from INT-6 to TS-7), which is inconceivable for a reaction conducted at 80 oC. In this view, I recommend that the authors should revise this issue and propose a more reasonable reaction path before the acceptance.
Other issues should also be addressed: 1) p-Methylbenzenesulfonohydrazide was used for the in situ formation of α-aryldiazomethane dipoles, have the authors tried hydrazine hydrate as its replacement? Hydrazine hydrate should be more green and practical compared with p-methylbenzenesulfonohydrazide. 2) Scheme 3, alkyl-substituted aldehydes should also be tested to probe the generality or limitation of this protocol. 3) Scheme 6, the free energy of INT-10 and INT-12 was wrong-labeled. 4) For the supporting information file, the spectra for many compounds contain obvious impurities, e.g. 4e, 4f, 4h, 4k, 4ae, 4ai, 4ak etc, which should be further re-purified.
Reviewer #3 (Remarks to the Author): Dear Editorial Team of Communications Chemistry, In attention to manuscript ID COMMSCHEM-22-0287-T entitled " Switchable Synthesis of Natural-Product-Like Lawsones and Indenopyrazoles through Regioselective Ring-Expansion of Indantrione", the authors present the synthesis of lawsone and indenopyrazole derivatives in aprotic (acetonitrile) and protic (alcohol) solvents through a new metal-free, ring-expansion reaction of indantrione with diazomethanes, generated in situ from the N-tosylhydrazones. The paper is complete. The authors explored all reaction pathways to demonstrate the mechanism of formation of the two products through an experimental and in silico study. Finally, they also demonstrated the synthetic versatility of lausone and indenopyrazoles. However, the synthesis of lausone derivatives of indantrione is not new and deserves mention. Schanck et al. reported a very similar reaction in Helv. Chim. Acta 2001, 84 (7) The responses to your comments are as follows.
Reviewer 1: Q-1) "Since scaffold generation is pivotal during the early stage of drug discovery, issues like chemical efficiency, and easy diversification are crucial in process development" Process development is ambiguous in this context -is it meant as large-scale drug manufacturing, or as reaction development?

Response:
Thanks for reviewer's comments. The "Process development" meant as reaction development. We have modified it in manuscript. Q-2) "classical homology method" --> "classical homologation method" Response: We have revised this error in manuscript.

YUNNAN UNIVERSITY
Kunming, Yunnan, The People's Republic of China, 650091 2 Q-3) "for generate structurally" --> "for generation of structurally" Response: We have revised this error in manuscript.
Q-4) Please expand Scheme 1 to include specific illustrations of previous approaches (e.g. from refs 4, 5, 6, 7). This will allow readers to better gauge the novelty of the current work.

Response:
We have expanded the Scheme 1 to include two specific examples. Q-5) " imbedded" --> "embedded" Response: We have corrected this error in manuscript. Q-6) "that aren't readily available" --> "that are not readily available"

Response:
We have corrected this error in manuscript. Q-7) "A small amount of selective by-product 4a was generated in 15% yield. " This is confusing -how can a by-product be selective?

Response:
Thanks for your suggestion, we have deleted 'chemoselective' in this sentence.

YUNNAN UNIVERSITY
Kunming, Yunnan, The People's Republic of China, 650091 3 Q-9) " Table 1 Optimized reaction conditions." -I do not think that this caption is appropriate, perhaps 'reaction optimization'?

Response:
Thanks for your suggestion, we have changed this caption to 'Reaction optimization'. Q-10) "To verity the relative configurations" --> "To verify the relative configurations"

Response:
We have corrected this error in manuscript.
Q-11) "facilely" -spelling Response: We have changed this word as "smoothly". Q-12) " labeling" -spelling Response: We have changed this word as "isotope-labeling". Q-13) Page 8, line 120: " using lawsone product 4a as the starting material, the reaction proceeded under the standard conditions in an alcohol solution." The phrasing here suggests that the reaction worked, but the scheme clearly shows that this reaction did not produce 5a. Please consider rephrasing.

Response:
We have corrected this misdescription in manuscript. Q-16) Energies are quoted in text and schemes to 2 d.p. precision -this implies much higher accuracy than DFT can deliver. I believe the energies should be quoted to 1 d.p. precision.

Response:
The accuracy of energy involved in this article has been revised to 1 d.p. precision. 17) Scheme 5 -the highest barrier in DFT calculated pathway is 22.1 kcal/mol, which suggests the reaction can proceed at room temperature or maybe slightly above, but the reaction is run at 80C. Please speculate on the reasons behind this discrepancy.

Response:
At room temperature, the highest barrier in DFT calculation is 20.87 kcal/mol, However, no corresponding product was obtained in the experiment, The specific YUNNAN UNIVERSITY Kunming

YUNNAN UNIVERSITY
Kunming, Yunnan, The People's Republic of China, 650091 7 Response: We have re-purified compound 4k and updated yield and NMR spectra in SI.
Q-27) Page 80 of the SI -the integration of the methyl peak in the 1H NMR is particularly bad. It is obvious only a tiny sliver of the actual peak has been integrated.
Please reprocess the NMR.

Response:
We have adjusted the integration of 4p in SI. Q-28) Page 84 -CN-compound needs repurification and yield adjustment, NMR clearly shows impure sample.

Response:
We have re-purified compound 4s and updated yield and NMR spectra in SI.

Response:
We have repurified compound 4ak and updated yield and NMR spectra in SI.
Q-30) Gaussian reference is incomplete -their website provides the preferred format for referencing the software.

Response:
Gaussian reference format has been supplemented completely. Q-31) I strongly encourage the authors to upload their computational output files as a dataset to a site like https://zenodo.org/ , or a similar open data repository and include the DOI link the dataset in the revised manuscript. Alternatively, the output files could

YUNNAN UNIVERSITY
Kunming, Yunnan, The People's Republic of China, 650091 8 be included as a data archive and attached as part of the SI. Sharing the output files makes the work more accessible and easier to reproducible and build upon, thus increasing its impact. The Cartesian coordinates are difficult to use, contains much more limited data, and presents an unnecessary barrier to reproduction of the results.

Response:
The computational output files have been uploaded to the open database https://zenodo.org/, and the DOI link the dataset is inserted into the calculation details in the SI Reviewer 2: Q-1) p-Methylbenzenesulfonohydrazide was used for the in situ formation of α-aryldiazomethane dipoles, have the authors tried hydrazine hydrate as its replacement? Hydrazine hydrate should be more green and practical compared with p-methylbenzenesulfonohydrazide.

Response:
Thanks for reviewer's comments. We have tried replacing p-toluenesulfonyl hydrazide with hydrazine hydrate, but unfortunately, we did not get satisfying results. Q-2) Scheme 3, alkyl-substituted aldehydes should also be tested to probe the generality or limitation of this protocol.

Response:
Thanks for your suggestion, we screened prenylaldehyde, butyraldehyde and 2-ethylcaproaldehyde in this reaction, unfortunately, alkyl-substituted aldehydes were found to be incompatible with this transformation and did not yield any product, even after stirring for more than 24 h. We have made comments in the manuscript.
Q-3) Scheme 6, the free energy of INT-10 and INT-12 was wrong-labeled.